700
Vol. 51, No. 6
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(6-benzylcarbamoyl-2-ben-
zothiazolylthio)acetamide (1o) This was prepared from benzylamine
(36%, colorless solid): 1H-NMR (CDCl3) d: 1.31—1.49 (2H, m), 1.78—
1.91 (2H, m), 2.02—2.18 (2H, m), 2.48—2.65 (2H, m), 3.30 (2H, s), 3.69—
3.86 (1H, m), 3.94 (2H, s), 4.68 (2H, d, Jϭ5.6 Hz), 6.48 (1H, t, Jϭ5.6 Hz),
7.06 (1H, d, Jϭ8.2 Hz), 7.20—7.42 (8H, m), 7.78—7.88 (2H, m), 8.31 (1H,
s); HR-MS m/z: 599.1097 (Calcd for C29H29N4O2Cl2S2, (MϩH)ϩ:
599.1109).
purified by silica gel column chromatography (2% MeOH in CHCl3) to give
1j (217 mg, 98%) as a colorless solid: 1H-NMR (CDCl3) d: 1.32—1.52 (2H,
m), 1.43 (3H, t, Jϭ7.1 Hz,), 1.80—1.92 (2H, m), 2.00—2.20 (2H, m),
2.45—2.68 (2H, m), 3.29 (2H, s), 3.70—3.90 (1H, m), 3.96 (2H, s), 4.43
(2H, d, Jϭ7.1 Hz), 7.00—7.10 (1H, m), 7.20—7.40 (3H, m), 7.87 (1H, d,
Jϭ8.6 Hz), 8.16 (1H, dd, Jϭ1.6, 8.9 Hz), 8.52 (1H, d, Jϭ1.6 Hz); HR-MS
m/z: 538.0792 (Calcd for C24H26N3O3Cl2S2, (MϩH)ϩ: 538.0793).
The following compounds (1f—i) were prepared in a manner similar to
the procedure described for 1j by using the amine 3a or 3b and an appropri-
ate acid.
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-[6-(2-pyridylmethyl)car-
bamoyl-2-benzothiazolylthio]acetamide (1p) This was prepared from 2-
1
(aminomethyl)pyridine (40%, colorless solid): H-NMR (CDCl3) d: 1.34—
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(2-benzothiazolyloxy)ac-
etamide (1f) This was prepared from (2-benzothiazolyloxy)acetic acid
1.50 (2H, m), 1.75—1.91 (2H, m), 2.02—2.19 (2H, m), 2.45—2.68 (2H, m),
3.29 (2H, s), 3.68—3.87 (1H, m), 3.95 (2H, s), 4.79 (2H, d, Jϭ4.3 Hz), 7.06
(1H, d, Jϭ8.2 Hz), 7.19—7.38 (5H, m), 7.65—7.80 (2H, m), 7.85—8.00
(2H, m), 8.38 (1H, s), 8.58 (1H, d, Jϭ4.0 Hz); HR-MS m/z: 600.1044 (Calcd
for C28H28N5O2Cl2S2, (MϩH)ϩ: 600.1061).
1
(4b) and 3a (64%, colorless oil): H-NMR (CDCl3) d: 1.40—1.64 (2H, m),
1.86—2.05 (2H, m), 2.05—2.22 (2H, m), 2.62—2.85 (2H, m), 3.41 (2H, s),
3.82—4.00 (1H, m), 5.02 (2H, s), 6.25 (1H, d, Jϭ8.2 Hz), 7.12 (1H, dd,
Jϭ2.0, 8.2 Hz), 7.22—7.50 (4H, m), 7.64—7.80 (2H, m); HR-MS m/z:
450.0804 (Calcd for C21H22N3O2Cl2S, (MϩH)ϩ: 450.0810).
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-[6-(3-pyridylmethyl)car-
bamoyl-2-benzothiazolylthio]acetamide (1q) This was prepared from 3-
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(2-benzothiazolylsulfinyl)ac-
etamide (1g) This was prepared from (2-benzothiazolylsulfinyl)acetic acid
1
(aminomethyl)pyridine (8%, colorless solid): H-NMR (CDCl3) d: 1.32—
1
1.50 (2H, m), 1.79—1.91 (2H, m), 2.03—2.20 (2H, m), 2.51—2.67 (2H, m),
3.31 (2H, s), 3.70—3.90 (1H, m), 3.95 (2H, s), 4.71 (2H, d, Jϭ5.5 Hz), 6.56
(1H, t, Jϭ5.5 Hz), 7.07 (1H, d, Jϭ1.9, 8.2 Hz), 7.20—7.41 (4H, m), 7.74
(1H, d, Jϭ7.9 Hz), 7.83 (1H, dd, Jϭ1.6, 8.5 Hz), 7.88 (1H, d, Jϭ8.5 Hz),
8.32 (1H, d, Jϭ1.6 Hz), 8.57 (1H, dd, Jϭ1.4, 4.7 Hz), 8.64 (1H, s); HR-MS
m/z: 600.1073 (Calcd for C28H28N5O2Cl2S2, (MϩH)ϩ: 600.1061).
(4c) and 3a (59%, colorless solid): H-NMR (CDCl3) d: 1.36—1.54 (2H,
m), 1.70—2.20 (4H, m), 2.60—2.80 (2H, m), 3.41 (2H, s), 3.70—3.90 (1H,
m), 3.88 (1H, d, Jϭ14.7 Hz), 4.12 (1H, d, Jϭ14.7 Hz), 6.86 (1H, d,
Jϭ7.7 Hz,), 7.13 (1H, dd, Jϭ1.9, 8.2 Hz), 7.37 (1H, d, Jϭ8.2 Hz), 7.41 (1H,
d, Jϭ1.9 Hz), 7.51 (1H, t, Jϭ7.4 Hz), 7.58 (1H, t, Jϭ7.4 Hz), 7.99 (1H, d,
Jϭ7.4 Hz), 8.09 (1H, d, Jϭ7.4 Hz); HR-MS m/z: 482.0537 (Calcd for
C21H22N3O2Cl2S2, (MϩH)ϩ: 482.0531).
N-(Piperidin-4-yl)-(2-benzothiazolylthio)acetamide (2) To a stirred so-
lution of 4a (450 mg, 2.00 mmol) and 4-amino-1-tert-butoxycarbonylpiperi-
dine (6)15) (400 mg, 2.00 mmol) in CHCl3 (20 ml) were added HOBt
(400 mg, 2.96 mmol) and WSC·HCl (575 mg, 3.00 mmol) at room tempera-
ture. After stirring for 20 h, the reaction mixture was diluted with EtOAc,
washed with saturated NaHCO3 solution, 10% citric acid solution, and
water, dried (MgSO4), and concentrated in vacuo. The residue was purified
by silica gel column chromatography (50—70% EtOAc in n-hexane) to give
N-(1-tert-butoxycarbonylpiperidin-4-yl)-(2-benzothiazolylthio)acetamide
(814 mg, 100%) as a colorless solid. A solution of the solid (814 mg,
2.00 mmol) in 10% HCl–MeOH (20 ml) was stirred at room temperature for
20 h. The mixture was concentrated in vacuo, and the residue was basified
with 1 M NaOH, and extracted with CHCl3. The organic layer was dried
(MgSO4) and concentrated in vacuo to give 2 (485 mg, 79%) as a colorless
solid: 1H-NMR (CDCl3) d: 1.18—1.37 (2H, m,), 1.80—1.94 (2H, m),
2.59—2.72 (2H, m), 2.92—3.05 (2H, m), 3.78—3.94 (1H, m), 3.92 (2H, s),
7.35 (1H, t, Jϭ7.8 Hz), 7.45 (1H, t, Jϭ7.8 Hz), 7.45—7.70 (1H, m), 7.78
(1H, d, Jϭ7.8 Hz), 7.84 (1H, d, Jϭ7.8 Hz).
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(2-benzothiazolylsulfonyl)ac-
etamide (1h) This was prepared from (2-benzothiazolylsulfonyl)acetic
acid (4d) and 3a (48%, colorless oil): 1H-NMR (CDCl3) d: 1.42—1.64 (2H,
m), 1.70—2.00 (2H, m), 2.05—2.22 (2H, m), 2.60—2.80 (2H, m), 3.41 (2H,
s), 3.70—3.89 (1H, m), 4.39 (2H, s), 6.68 (1H, d, Jϭ7.8 Hz), 7.13 (1H, dd,
Jϭ2.0, 8.2 Hz), 7.37 (1H, d, Jϭ8.2 Hz), 7.41 (1H, d, Jϭ2.0 Hz), 7.58—7.72
(2H, m), 8.02 (1H, dd, Jϭ2.0, 7.2 Hz), 8.21 (1H, dd, Jϭ2.0, 7.2 Hz); HR-MS
m/z: 498.0508 (Calcd for C21H22N3O3Cl2S2, (MϩH)ϩ: 498.0480).
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-N-methyl-(2-benzothia-
zolylthio)acetamide (1i) This was prepared from 4a and 3b (81%, color-
1
less solid): H-NMR (CDCl3) d: 1.50—2.18 (6H, m), 2.78—2.95 (2H, m),
2.89 & 3.06 (3H, s), 3.36 & 3.43 (2H, s), 3.72—3.85 & 4.39—4.57 (1H, m),
4.39 & 4.44 (2H, s), 7.08—7.18 (1H, m), 7.23—7.48 (4H, m), 7.72—7.99
(2H, m); HR-MS m/z: 480.072 (Calcd for C22H24N3OCl2S2, (MϩH)ϩ:
480.0738).
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(6-carboxyl-2-benzothia-
zolylthio)acetamide (5) To a stirred solution of 1j (200 mg, 0.37 mmol) in
THF (2.0 ml) and MeOH (2.0 ml) was added 1 M NaOH solution (0.50 ml,
0.50 mmol) at room temperature. After stirring for 3 h, the residue was ad-
justed to pH 5—6 with 1 M HCl, extracted with EtOAc, washed with brine,
and dried (MgSO4). The solvent was removed in vacuo to give 5 (140 mg,
74%) as pale yellow solid, which was used for the next step without further
purification.
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(6-carbamoyl-2-benzothia-
zolylthio)acetamide (1l) This was prepared in a similar manner to the pro-
cedure described for 1j by using 5 and ammonium chloride. (5%, colorless
solid): 1H-NMR (CDCl3) d: 1.32—1.50 (2H, m), 1.79—1.91 (2H, m),
2.02—2.18 (2H, m), 2.48—2.67 (2H, m), 3.30 (2H, s), 3.70—3.88 (1H, m),
3.94 (2H, s), 5.50—6.34 (2H, m), 7.06 (1H, d, Jϭ8.0 Hz), 7.19—7.38 (3H,
m), 7.81—7.90 (2H, m), 8.33 (1H, s); HR-MS m/z: 509.0634 (Calcd for
C22H23N4O2Cl2S2, (MϩH)ϩ: 509.0640).
The following compounds (1m—q) were prepared in a manner similar to
the procedure described for 1l by using 5 and an appropriate amine.
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(6-methylcarbamoyl-2-ben-
zothiazolylthio)acetamide (1m) This was prepared from methylamine hy-
drochloride (7%, colorless solid): 1H-NMR (CDCl3) d: 1.32—1.56 (2H, m),
1.79—1.92 (2H, m), 2.03—2.20 (2H, m), 2.50—2.68 (2H, m), 3.06 (3H, d,
Jϭ4.9 Hz), 3.31 (2H, s), 3.70—3.88 (1H, m), 3.95 (2H, s), 6.10—6.25 (1H,
m), 7.07 (1H, d, Jϭ8.2 Hz), 7.19—7.39 (3H, m), 7.79 (1H, dd, Jϭ1.7,
8.5 Hz), 7.87 (1H, d, Jϭ8.5 Hz), 8.29 (1H, d, Jϭ1.7 Hz); HR-MS m/z:
523.0820 (Calcd for C23H25N4O2Cl2S2, (MϩH)ϩ: 523.0796).
N-[1-(3,4-Dichlorobenzyl)piperidin-4-yl]-(6-dimethylcarbamoyl-2-
benzothiazolylthio)acetamide (1n) This was prepared from dimethyl-
amine hydrochloride (2%, colorless solid): 1H-NMR (CDCl3) d: 1.31—1.50
(2H, m), 1.80—1.92 (2H, m), 2.03—2.19 (2H, m), 2.50—2.69 (2H, m),
2.95—3.20 (6H, m), 3.33 (2H, s), 3.71—3.85 (1H, m), 3.94 (2H, s), 7.03—
7.12 (1H, m), 7.29—7.40 (3H, m), 7.49—7.54 (1H, m), 7.80—7.90 (2H, m);
HR-MS m/z: 537.0981 (Calcd for C24H27N4O2Cl2S2, (MϩH)ϩ: 537.0953).
4-Amino-1-(3,4-dichlorobenzyl)piperidine (3a) To a solution of 7
(6.0 g, 30 mmol) in CHCl3 (80 ml) was added 3,4-dichlorobenzaldehyde
(6.3 g, 36 mmol) and NaBH(OAc)3 (7.6 g, 36 mmol) at room temperature,
and the mixture was stirred for 20 h. After the addition of saturated NaHCO3
solution, the mixture was extracted with CHCl3. The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was purified by silica gel
column chromatography (25—50% EtOAc in n-hexane) to give 4-tert-bu-
toxycarbonylamino-1-(3,4-dichlorobenzyl)piperidine (6.9 g, 64%) as a col-
orless solid. A solution of the solid (6.9 g, 19.2 mmol) in 10% HCl–MeOH
(50 ml) was stirred at room temperature for 20 h. The mixture was concen-
trated in vacuo, and the residue was basified 1 M NaOH and extracted with
CHCl3. The organic layer was dried (MgSO4) and concentrated in vacuo to
1
give 3a (4.23 g, 85%) as a colorless oil: H-NMR (CDCl3) d: 1.31—1.48
(2H, m), 1.75—1.87 (2H, m), 1.96—2.10 (2H, m), 2.60—2.84 (3H, m), 3.42
(2H, s), 7.15 (1H, dd, Jϭ2.0, 8.2 Hz), 7.37 (1H, d, Jϭ8.2 Hz), 7.42 (1H, d,
Jϭ2.0 Hz).
1-(3,4-Dichlorobenzyl)-4-(methylamino)piperidine (3b) To a solution
of 7 (2.0 g, 10 mmol) in CHCl3 (40 ml) was added 3,4-dichlorobenzaldehyde
(1.9 g, 10.8 mmol) and NaBH(OAc)3 (3.2 g, 15 mmol) at room temperature,
and the mixture was stirred for 20 h. After the addition of saturated NaHCO3
solution, the mixture was extracted with CHCl3. The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was purified by silica gel
column chromatography (25—50% EtOAc in n-hexane) to give 4-tert-bu-
toxycarbonylamino-1-(3,4-dichlorobenzyl)piperidine (2.6 g, 72%) as a col-
orless solid. To a stirred solution of the solid (51 mg, 0.142 mmol) in THF
(1.0 ml) was added 60% NaH in oil (10 mg, 0.25 mmol) at room tempera-
ture, and the resulting solution was stirred at the same temperature for
30 min. To this solution was added MeI (50 ml, 0.80 mmol), and the mixture
was stirred for 3.5 h. The reaction was quenched by adding saturated
NaHCO3, and the mixture was extracted with EtOAc. The organic layer was
washed with water, dried (MgSO4), and concentrated in vacuo. The residue